Enhancement of antipsychotic-like properties of the dopamine D2 receptor antagonist, raclopride, by the additional treatment with the 5-HT2 receptor blocking agent, ritanserin, in the rat

The effects of 5-HT₂ receptor blockade on the ability of a dopamine (DA) D₂ receptor antagonist to produce suppression of conditioned avoidance response (CAR) and to produce catalepsy in rats were examined. It was found that ritanserin (2 mg kg⁻¹ s.c.) enhanced the raclopride (0.1 mg kg⁻¹ s.c.)-induced suppression of CAR without affecting raclopride-induced catalepsy at either maximal (4 mg kg⁻¹ s.c.) or submaximal (0.2 mg kg⁻¹ s.c.) doses. Considering the CAR performance as an index of mesocorticolimbic dopaminergic functions, it is concluded that 5-HT₂ receptor blockade confers a limbic profile on the DA D₂ receptor antagonist.     

Effects of raclopride on exploratory locomotor activity, treadmill locomotion, conditioned avoidance behaviour and catalepsy in rats: behavioural profile comparisons between raclopride, haloperidol and preclamol

Raclopride, a new potential antipsychotic agent blocking central dopamine (D2) receptors, was found to suppress exploratory locomotor activity, treadmill locomotion and conditioned avoidance response in rats. The threshold dose for effects in these test situations was about 0.5 mg/kg intraperitoneally. A considerably higher dose, 16 mg/kg intraperitoneally, was needed to produce maximal catalepsy. Maximal effects were obtained within 1-2 hrs and the duration of the effect was 2-8 hrs, depending on the test situation. The behavioural profile of raclopride is different from the classic antipsychotic haloperidol, blocking central dopamine (DA) receptors, as well as from the partial DA agonist preclamol, which inhibits central DA neurotransmission by activating DA autoreceptors. Thus, although similar to haloperidol in other respects, comparatively high doses of raclopride are needed to produce catalepsy, indicating less propensity to produce severe extrapyramidal side effects. Raclopride and preclamol are about equipotent in suppressing exploratory locomotor activity. However, raclopride is more potent than preclamol in suppressing treadmill locomotion, conditioned avoidance behaviour and catalepsy.     

Topiramate augments the antipsychotic-like effect and cortical dopamine output of raclopride

Recent clinical studies have shown that the anticonvulsant drug topiramate may improve negative symptoms in schizophrenia when added to a stable regimen of neuroleptic medication. It has also been shown that addition of topiramate to neuroleptics might be beneficial in treatment-resistant schizophrenia. Clinically effective doses of antipsychotic drugs (APDs) have been found to suppress conditioned avoidance response behavior (CAR), a preclinical test of antipsychotic activity with high predictive validity, in rats. Therefore, we investigated the putative antipsychotic-like activity of topiramate when added to the selective dopamine (DA) D₂ receptor antagonist raclopride, using the CAR model in the rat. Extrapyramidal side effect liability of the drug combination was evaluated in parallel by means of the catalepsy test. We also examined the effect of this drug treatment on DA release in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), using in vivo microdialysis in freely moving animals. Topiramate (40 mg/kg), while ineffective when given alone, significantly augmented the antipsychotic-like effect of raclopride (0.075 mg/kg) on CAR without any concomitant catalepsy. Addition of topiramate to rats treated with raclopride generated a large increase in DA output in the mPFC, whereas no additional effect on the raclopride-induced DA release in the NAC was obtained. These data support the adjunctive use of topiramate in schizophrenia to ameliorate negative symptoms and suggest that this treatment may increase the efficacy, but not the extrapyramidal side effect liability, of the APDs used.     

Quinpirole, 8-OH-DPAT and ketanserin modulate catalepsy induced by high doses of atypical antipsychotics

The effect of the selective dopamine D2 receptor agonist quinpirole, the selective 5-HT1A receptor agonist 8-OH-DPAT and the selective 5-HT2A receptor antagonist ketanserin on catalepsy induced by atypical antipsychotics clozapine, risperidone, olanzapine and sertindole at higher doses was studied in rats. Haloperidol (0.5, 1 and 2 mg/kg), clozapine (50 and 75 mg/kg) and olanzapine (15 and 30 mg/kg) produced catalepsy dose-dependently while sertindole at doses up to 40 mg/kg failed to produce catalepsy in rats. However, sertindole (15, 30 and 45 mg/kg) produced a cataleptic effect in mice in a dose-dependent manner. At a high dose (5 mg/kg), risperidone produced catalepsy in rats. Quinpirole (0.05 and 0.1 mg/kg) reversed the cataleptic effect of haloperidol (2 mg/kg), risperidone (5 mg/kg), olanzapine (30 mg/kg) and sertindole (45 mg/kg). Quinpirole (0.05 and 0.1 mg/kg) reversed clozapine (75 mg/kg)-induced catalepsy. 8-OH-DPAT (0.15 and 0.3 mg/kg) dose-dependently reversed catalepsy induced by haloperidol (2 mg/kg) and risperidone (5 mg/kg) without affecting the cataleptic effect of olanzapine. However, the higher dose (0.45 mg/kg) of 8-OH-DPAT reversed it significantly. 8-OH-DPAT (0.3 mg/kg) reversed clozapine (75 mg/kg)-induced catalepsy. 8-OH-DPAT (0.15, 0.3 and 0.45 mg/kg) failed to reverse sertindole-induced catalepsy. Ketanserin (0.75 and 1.5 mg/kg) completely reversed catalepsy induced by haloperidol (2 mg/kg) and risperidone (5 mg/kg). Ketanserin (0.75 and 1.5 mg/kg) dose-dependently reversed olanzapine (30 mg/kg) and sertindole (45 mg/kg)-induced catalepsy without any effect on clozapine (75 mg/kg)-induced catalepsy. A higher dose (3 mg/kg) of ketanserin reversed clozapine-induced catalepsy. The present study suggests that atypical antipsychotics show fewer extrapyramidal symptoms (EPS) due to greater modulation of the serotonergic system. Therefore, an antipsychotic with dopamine D2/5-HT2A antagonistic action and 5-HT1A agonistic action may prove to be superior to the existing antipsychotics.     

Long-term treatment with low doses of the D1 antagonist NNC 756 and the D2 antagonist raclopride in monkeys previously exposed to dopamine antagonists

EightCebus apella monkeys previously exposed to D₁ and D₂ antagonists were treated subcutaneously for 8 weeks with the D₁ antagonist NNC 756 (0.01mg/kg), followed by a wash-out period of 4 weeks and treatment with the D₂ antagonist raclopride for 8 weeks (end doses 0.01 mg/kg). NNC 756 induced no dystonia, while marked dystonia was induced by raclopride. Mild tolerance to the dystonia-inducing effect of raclopride slowly developed. Both drugs induced significant sedation and mild bradykinesia. Sedation induced by NNC 756 was stronger than that of raclopride, while no differences were found regarding bradykinesia. The sedative effect of both NNC 756 and raclopride increased over time during chronic treatment. No changes in bradykinesia developed. No significant dyskinesia was induced by NNC 756, while raclopride significantly induced both acute and tardive oral dyskinesia. Furthermore, raclopride-induced acute dyskinesia worsened during chronic treatment. Concomitant treatment with NNC 756 tended to reduce the D₁ agonist SKF 81297-induced dyskinesia and grooming, while concomitant treatment with raclopride increased SKF 81297-induced dyskinesia and tended to decrease SKF 81297-induced grooming. Chronic treatment with raclopride induced supersensitivity to both the D₂/D₃ agonist LY 171555 and SKF 81297, while chronic NNC 756 treatment only induced supersensitivity to SKF 81297. The findings indicate that D₁ antagonists may induce less dystonia and oral dyskinesia as compared with D₂ antagonists and support the hypothesis of both a permissive and an inhibitory interaction between D₁ and D₂ receptor systems.     

Clozapine inhibits catalepsy induced by olanzapine and loxapine, but prolongs catalepsy induced by SCH 23390 in rats

Loxapine (0.3mg/kg s.c.), olanzapine (10 mg/ kg s.c.) and SCH 23390 (R-(+)-chloro-2, 3, 4, 5-tetrahydro-3-methyl-5-phenyl-1-H-3-benzazepine; 1mg/kg, s.c.), but not clozapine (10mg/kg, s.c.), induced catalepsy in rats. Co-administration of clozapine (1, 3 and 10mg/ kg s.c.) dose-dependently inhibited loxapine-induced catalepsy. Clozapine (10mg/kg s.c.) also prevented the induction of catalepsy by olanzapine. In addition, clozapine abolished the catalepsy induced by loxapine when it was administered after the response had fully developed. In contrast, the duration of SCH 23390-induced catalepsy was prolonged by clozapine, indicating that its anti-catalepsy effects against olanzapine and loxapine are unlikely to be caused by muscle relaxation, sedation or stimulation. Since SCH 23390-induced catalepsy is reported to be blocked by scopolamine, dizocilpine (MK-801) or 8-hydroxy-dipropylamino-tetralin, it is unlikely that muscarinic blockade, NMDA ion channel blockade and 5-HT_1A receptor agonism, respectively, are involved in clozapine’s action, but the mechanism by which clozapine exerts this anti-cataleptic effect remains unknown. Received: 8 August 1996 / Accepted: 10 December 1996     

Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunctive alpha2 adrenoceptor blockade: experimental evidence

Adjunctive treatment with the selective alpha2 adrenoceptor antagonist idazoxan augments the effect of conventional antipsychotics in treatment-resistant schizophrenics comparing favourably with clozapine. Clozapine has high affinity for alpha2 adrenoceptors. Previously, we found that adjunctive idazoxan treatment to the dopamine (DA) D2/3 antagonist raclopride enhanced raclopride-induced effects in an animal model of antipsychotic activity (conditioned avoidance response, CAR) and, similarly to clozapine, reversed the disruption of working memory induced by N-methyl-D-aspartate receptor blockade in rats with a concomitant increase in prefrontal DA efflux. To further investigate the significance of alpha2 adrenoceptor affinity for antipsychotic efficacy, we here investigated, in rats, the effects of adjunctive idazoxan treatment to low doses of a typical (haloperidol) and an atypical (olanzapine) antipsychotic drug, both lacking appreciable alpha2 adrenoceptor affinity, on (i) CAR; (ii) catalepsy; and (iii) DA output in the prefrontal cortex and the nucleus accumbens using microdialysis. Adjunctive treatment with idazoxan to haloperidol or olanzapine enhanced suppression of CAR to a level predicting sufficient antipsychotic activity, increased DA output preferentially in the prefrontal cortex, and reversed haloperidol-induced catalepsy. Our data confirm and extend our previous findings as well as clinical observations, and suggest that adjunctive alpha2 adrenoceptor blockade both typical and atypical antipsychotic drugs, lacking appreciable affinity for the alpha2 adrenoceptor, may contribute to a more advantageous therapeutical profile of these drugs in schizophrenia treatment, allowing for reduced DA D2 occupancy and reduction of unwanted side-effects.     

Trough oestradiol levels associated with cognitive impairment in post-menopausal women after 10 years of oestradiol implants

RATIONALE: Clozapine is a unique antipsychotic with very low propensity to cause motor side effects. In contrast to most other antipsychotics that block more than 70% of dopamine D(2) receptors at therapeutic doses, clozapine occupies less than 70%. Furthermore, even at maximum occupancy, 70% is not exceeded. Several mechanisms have been proposed as explanations for this low D(2) receptor occupancy, but clear evidence is limited. OBJECTIVES: In patient studies the data are limited by the dose-range that can be safely used; therefore, the aims of this study were to examine the maximum occupancy of dopamine D(2) receptors with up to 5.0 mg/kg of bolus injection of clozapine to non-human primates and to measure the time course of occupancy. METHODS: PET examination with [(11)C]raclopride was performed to measure the dopamine D(2) receptor occupancy in the striatum of two monkeys after the bolus injection of 0.2-5.0 mg/kg clozapine. [(11)C]raclopride was injected sequentially to follow the time course of occupancy up to 7 h after the clozapine injection. RESULTS: Dopamine D(2) receptor occupancy reached up to 83% after 5.0 mg/kg clozapine injection. Occupancy decreased with a half-life of 7.22 h after 5.0 mg/kg clozapine and 5.25 h after 1.0 and 2.0 mg/kg clozapine. CONCLUSIONS:Clozapine could occupy a high proportion of dopamine D(2) receptors. The time course of occupancy was relatively fast, with a half-life of several hours.     

Anti-cataleptic effects of clozapine, but not olanzapine and quetiapine, on SCH 23390- or raclopride-induced catalepsy in rats.

The present study investigated potential anti-cataleptic properties of the prototype atypical antipsychotic clozapine and two newly developed atypical antipsychotics, olanzapine and quetiapine, which are structurally related and display similar pharmacological profiles to clozapine. Clozapine (2.5 mg kg(-1), s.c.), but not olanzapine (2.0 mg kg(-1), s.c.) and quetiapine (20.0 mg kg(-1), s.c.), blocked catalepsy induced either by the dopamine D(1/5) receptor antagonist SCH 23390 (50.0 microg kg(-1), s.c) or the selective dopamine D(2/3) receptor antagonist raclopride (4.0 mg kg(-1), s.c.). Such findings are consistent with the beneficial effects of clozapine in the management of drug-induced psychosis in parkinsonian patients, and suggest that neither olanzapine nor quetiapine may be a safe alternative to clozapine in this field. Furthermore, the results indicate that clozapine has a unique pharmacological profile that distinguishes it from olanzapine and quetiapine. The mechanisms underlying anti-cataleptic or anti-parkinsonian properties of clozapine are unclear but may be related to dopamine D(1) receptor agonism of clozapine.     

Apomorphine-induced behavioural sensitization in rats: individual differences, role of dopamine and NMDA receptors

Apomorphine-induced behavioural sensitization was studied in male Wistar rats. The acute administration of apomorphine (0.5 mg/kg s.c.), a dopamine agonist, did not affect the locomotor activity of rats, but it caused stereotyped behaviour characterized by repeated gnawing, licking and sniffing. A significant increase in the locomotor activity became evident after repeated treatments with apomorphine (0.5 mg/kg twice daily for 14 days). However, there were marked individual differences in the sensitization of rats to apomorphine. One third of animals did not react with increased locomotor activity even after the 2-week administration of apomorphine, whereas the other one third needed only a few injections to display increased behavioural response to apomorphine. The behavioural response of the remaining one third of rats was between weak and strong responders. Simultaneously, the stereotyped behaviour occurred earlier and its intensity tended to be lower after repeated treatment with apomorphine. Nevertheless, the established changes of stereotyped behaviour did not correlate with the increase of locomotor activity. The administration of amphetamine (2.5 mg/kg, s.c.), an indirect dopamine agonist, but not a non-competitive NMDA antagonist dizocilpine (0.25 mg/kg i.p.), tended to cause a similar response profile with apomorphine in sensitized rats. The ED₅₀ values of the dopamine antagonists blocking apomorphine-induced increase in the locomotor activity were the following: 0.09 mg/kg for raclopride (dopamine D₂ antagonist), 0.023 mg/kg for SCH 23390 (dopamine D₁ antagonist), 6.42 mg/kg for clozapine (dopamine D₄ antagonist). This supports the involvement of D₁ and D₂ receptors in the expression of apomorphine-induced behavioural sensitization. The concomitant administration of dizocilpine (0.5 mg/kg), SCH 23390 (0.05 mg/kg), raclopride (0.1 mg/kg) and clozapine (20 mg/kg) with apomorphine (0.5 mg/kg twice daily for 2 weeks) antagonized the development of behavioural sensitization to apomorphine. Accordingly, at least three different molecular targets, namely dopamine D₁ and D₂, and NMDA receptors, are involved in the development of apomorphine-induced behavioural sensitization.     

Noradrenaline reuptake inhibition enhances the antipsychotic-like effect of raclopride and potentiates D2-blockage-induced dopamine release in the medial prefrontal cortex of the rat.

We have previously observed that addition of an alpha(2)-adrenoceptor antagonist to a selective dopamine (DA) D(2) receptor antagonist enhances the antipsychotic-like effect of the D(2) blocker and also selectively increases DA output in the medial prefrontal cortex (mPFC) in rats. These data also correlate well with previous clinical trials showing augmentation by an equivalent drug combination in schizophrenia. Since the selective noradrenaline reuptake inhibitor reboxetine was found to cause similar effects on the mesolimbocortical DA system as alpha(2)-adrenoceptor antagonists, the present study was undertaken to explore whether also reboxetine might augment the effect of the DA D(2) receptor antagonist raclopride in the same preclinical model of antipsychotic activity, the conditioned avoidance response (CAR) test. We also investigated the effect of this combination in the catalepsy test for extrapyramidal side effect liability, as well as on DA output in the mPFC and the nucleus accumbens, respectively. Reboxetine (6 mg/kg, i.p.) significantly enhanced the suppressant effect of raclopride (0.1 mg/kg, s.c.) on CAR without affecting catalepsy. Administration of raclopride (0.1 mg/kg, s.c.) to rats pretreated with reboxetine (6 mg/kg, i.p.) resulted in a greatly enhanced effect on DA output in the mPFC but not in the nucleus accumbens when compared with raclopride alone. Consequently, these results suggest that noradrenaline reuptake inhibition may provide means of augmenting the efficacy of classical D(2)-antagonists in the treatment of schizophrenia, and, in principle, to generate an atypical antipsychotic drug profile.     

Effect of chronic treatment with NNC 756, a new D-1 receptor antagonist, or raclopride, a D-2 receptor antagonist, in drug-naive Cebus monkeys: dystonia, dyskinesia and D-1/D-2 supersensitivity

When given subcutaneously in gradually increasing doses, up to 1 mg/kg, NNC 756, a dopamine (DA) D-1 antagonist, failed to produce dystonia in eight drug-naive Cebus monkeys. In contrast, raclopride, a DA D-2 antagonist, produced dystonia at low doses (0.010-0.015 mg/kg). Following pre-treatment with raclopride, NNC 756 also induced dystonia at low doses (0.015-0.025 mg/kg), but continued treatment caused tolerance, and increasing doses of NNC 756 could be administered without induction of dystonia. NNC 756 induced a dose-dependent parkinsonism (slow, stiff movements and tremor), and more sedation than raclopride. After treatment for 14 weeks, withdrawal of raclopride (0.01 mg/kg) led to mild oral dyskinesia (tardive dyskinesia), while withdrawal of NNC 756 (1.0 mg/kg) led to a special grooming syndrome, but no dyskinesia. Withdrawal of raclopride as well as NNC 756 led to behavioural D-1 and D-2 dopamine supersensitivity in the form of increased dyskinesia (including grooming after NNC 756) induced by D-1 agonist (SKF 81297) and increased arousal induced by D-2 agonist (quinpirole). These results indicate that D-1 antagonists such as NNC 756 elicit fewer extrapyramidal symptoms (both acute and tardive) than D-2 antagonists such as raclopride, although extremely high doses may cause a special grooming withdrawal syndrome.     

Feeding conditions differentially affect the neurochemical and behavioral effects of dopaminergic drugs in male rats

The high co-morbidity of eating disorders and substance abuse suggests that nutritional status can impact vulnerability to drug abuse. These studies used rats to examine the effects of food restriction on dopamine clearance in striatum and on the behavioral effects of amphetamine (locomotion, conditioned place preference), the dopamine receptor agonist quinpirole (yawning), and the dopamine receptor antagonist raclopride (catalepsy). Amphetamine increased locomotion and produced conditioned place preference. Food restriction reduced dopamine clearance, which was restored by repeated treatment with amphetamine or by free feeding. Food restriction also decreased sensitivity to quinpirole-induced yawning and raclopride-induced catalepsy; normal sensitivity to both drugs was restored by free feeding. The same amphetamine treatment that normalized dopamine clearance, failed to restore normal sensitivity to quinpirole or raclopride, suggesting that in food-restricted rats the activity of dopamine transporters and dopamine receptors is differentially affected by pathways that are stimulated by amphetamine. These studies show that modest changes in nutritional status markedly alter dopamine neurotransmission and the behavioral effects of direct-acting dopamine receptor drugs (agonist and antagonist). These results underscore the potential importance of nutritional status (e.g., glucose and insulin) in modulating dopamine neurotransmission and in so doing they begin to establish a neurochemical link between the high co-morbidity of eating disorders and drug abuse.     

Haloperidol conditioned catalepsy in rats: a possible role for D1-like receptors

Decreases in brain dopamine (DA) lead to catalepsy, quantified by the time a rat remains with its forepaws resting on a suspended horizontal bar. Low doses of the DA D2 receptor-preferring antagonist haloperidol repeatedly injected in a particular environment lead to gradual day-to-day increases in catalepsy (catalepsy sensitization) and subsequent testing following an injection of saline reveal conditioned catalepsy. We tested the hypothesis that D1-like and D2 receptors play different roles in catalepsy sensitization and in acquisition and expression of conditioned catalepsy. Rats were repeatedly treated with the DA D1-like receptor antagonist SCH 23990 (0.05, 0.1 and 0.25 mg/kg i.p.), the D2 receptor-preferring antagonist haloperidol (0.1, 0.25 and 0.5 mg/kg i.p.) or a combination of the two drugs and tested for catalepsy each day in the same environment. Following 10 drug treatment days, rats were injected with saline and tested for conditioned catalepsy in the previously drug-paired environment. Haloperidol did not elicit cataleptic responses in the initial session; however, rats developed sensitization with repeated testing. Significant catalepsy sensitization was not observed in rats repeatedly tested with SCH 23390. When rats were injected and tested with saline following haloperidol sensitization they exhibited conditioned catalepsy in the test environment; conditioned catalepsy was not seen following SCH 23390. Rats treated with 0.05 mg/kg SCH 23390+0.25 mg/kg haloperidol showed catalepsy sensitization but failed to show conditioned catalepsy. Conversely, SCH 23390 (0.05 mg/kg) given on the test day after sensitization to haloperidol (0.25 mg/kg) failed to block conditioned catalepsy. Repeated antagonism of D2 receptors leads to catalepsy sensitization with repeated testing in a specific environment. Conditioned catalepsy requires intact D1-like receptor function during sensitization sessions but not during test sessions. In conclusion, repeated antagonism of D2, but not D1-like receptors leads to catalepsy sensitization with repeated testing in a specific environment. Conditioned catalepsy requires functional D1-like receptors during sensitization sessions but not during test sessions.     

Dopamine D2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats

RATIONALE: Human positron emission tomography (PET) shows that striatal dopamine D2 receptor occupancy predicts extrapyramidal side effects (EPS). Patients showed a clinical response with > or = 65% D2 occupancy, but EPS only when D2 occupancy >78%. Catalepsy and the selective suppression of conditioned avoidance response (CAR) are often used as animal models to predict EPS and antipsychotic effect, respectively. However, the quantitative relationship between striatal D2 occupancy and effects in these models is not known. OBJECTIVES: The present study intended to investigate the relationship between animal catalepsy, suppression of CAR, and D2 receptor blockade using a method of evaluating D2 receptor occupancy similar in principle to that used in patients. METHODS: In vivo binding of [11C]-raclopride and [3H]-raclopride was compared. Doses of cold raclopride were chosen to provide a D2 occupancy from 0 to 95%. The relationship between dose/time course of catalepsy and D2 occupancy was assessed. Effects of raclopride on conditioned avoidance response (CAR) behavior were tested. RESULTS: In vivo binding of [11C]-raclopride compared to [3H]-raclopride was virtually the same. Using [3H]-raclopride, cold raclopride (0.01-0.2 mg/kg) produced 16-77% D2 receptor occupancy and no catalepsy. Raclopride (0.5-2 mg/kg) produced 83-95% D2 occupancy and significant catalepsy. Raclopride (2 mg/kg) produced on average 95% and 87% D2 receptor occupancy 1 and 2 h after administration, respectively, and maximum catalepsy. D2 occupancy at 4, 8 and 24 h was on average 58%, 46%, and 4%, respectively. No catalepsy was observed. Raclopride (0.2 mg/kg), estimated at 70-75% D2 occupancy, produced suppression of CAR. CONCLUSIONS: In vivo D2 occupancy measurements in rats using [3H]-raclopride is analogous to using [11C]-raclopride in human PET scanning. Suppression of CAR occurred at a D2 occupancy of around 70-75%, and catalepsy at D2 occupancy >80%. Results closely resembled human studies where 65-70% D2 occupancy was required for antipsychotic response, while > or = 80% D2 occupancy led to EPS. Brain mechanisms involved in mediation of catalepsy in rats and EPS in humans might indeed be similar. Both suppression of CAR in rats and antipsychotic response in humans might share an underlying construct, i.e. the need for around 70% D2 receptor blockade.     

Low-dose clozapine pretreatment partially prevents haloperidol-induced deficits in conditioned active avoidance

The effectiveness of neuroleptics in disrupting conditioned active avoidance has led to the widespread use of this test as an index of antipsychotic efficacy, whereas the tendency for these drugs to induce catalepsy is believed to reflect their propensity to cause extrapyramidal motor side-effects. Although the typical neuroleptic haloperidol produces catalepsy as well as profound deficits in conditioned active avoidance, the atypical neuroleptic clozapine does not induce catalepsy and is less effective than haloperidol in disrupting active avoidance. Furthermore, clozapine pretreatment prevents haloperidol-induced catalepsy. We investigated whether clozapine pretreatment might also reduce the disruptive effects of haloperidol on two-way active avoidance. We assessed the avoidance acquisition of the following drug treatment groups in which all animals received two injections prior to testing: vehicle + vehicle, vehicle + haloperidol (0.1 mg/kg, i.p.), clozapine (2.5, 5.0 or 10 mg/kg, i.p.) + haloperidol (0.1 mg/kg, i.p.), or clozapine (2.5, 5.0 or 10 mg/kg, i.p.) + vehicle. Haloperidol-pretreated animals showed markedly impaired active avoidance, deficits which were improved by 2.5 and 5 mg/kg but not by 10 mg/kg clozapine pretreatment. These data suggest that the disruptive effects of haloperidol on conditioned active avoidance partially mirror its capacity to induce catalepsy and extrapyramidal motor symptoms. Furthermore, this study indicates that clozapine may be effective in reducing motor side-effects caused by typical neuroleptics.     

In vitro and in vivo characterization of F-97013-GD, a partial 5-HT1A agonist with antipsychotic- and antiparkinsonian-like properties

In order to better define the role of 5-HT(1A) receptors in the modulation of extrapyramidal motor functions, we investigated the effect of 5-HT(1A) agonists on tacrine-induced tremulous jaw movements (TJM) in rats, a putative model of parkinsonian tremor. Acute injection of 5-HT(1A) agonists 8-OH-DPAT and buspirone dose-dependently counteracted the tacrine-induced oral movements (ED(50)=0.04 and 1.0mg/kg, respectively), an effect reversed by the selective 5-HT(1A) antagonist WAY 100,635. In contrast to classical antipsychotics, the atypical antipsychotics risperidone (ED(50)=0.3mg/kg) and clozapine (ED(50)=1.5mg/kg) blocked the oral movements induced by the cholinomimetic agent at or below the doses required for suppression of conditioned avoidance response. The compound F-97013-GD (6-methyl-2-[4-(naphtylpiperazin-1-yl)butyl]-3-(2H)-pyridazinone), a putative antipsychotic drug that in functional in vitro and in vivo assays behaved as a mixed dopamine D(2)-antagonist and 5-HT(1A)-partial agonist, also displayed a potent antitremorgenic effect in this paradigm (ED(50)=0.5mg/kg). Interestingly, pretreatment with WAY 100,635 blocked the inhibitory effect of F-97013-GD but not that of clozapine. The 5-HT depleting agent para-chlorophenylalanine (PCPA) partially attenuated tacrine-induced TJM but did not block the suppressive effect of 5-HT(1A) agonists. In addition, only high doses of F-97013-GD induced catalepsy in rodents and, like 8-OH-DPAT and clozapine, the compound reversed the haloperidol-induced catalepsy in rats. These results show that 5-HT(1A) receptors play a role in the regulation of tacrine-induced TJM and suggest that their activation by novel antipsychotics may not only reduce the extrapyramidal side effects EPS liability, but also be effective in the treatment of parkinsonian tremor.     

Generalization of clozapine as compared to other antipsychotic agents to a discriminative stimulus elicited by the serotonin (5-HT)2A antagonist,MDL100,907

Employing a two-lever, food-reinforced FR10 procedure, rats were trained to recognize a discriminative stimulus (DS) elicited by the 5-HT(2A) receptor antagonist and potential antipsychotic agent, MDL100,907 (0.16 mg/kg, i.p.). In generalization tests, by analogy to MDL100,907 itself (Effective Dose(50) (ED(50)), 0.002 mg/kg, s.c.), the 'atypical' antipsychotic, clozapine, which displays high affinity for 5-HT(2A) as compared to D(2) receptors, dose-dependently and fully generalized to MDL100,907 (ED(50), 0.2 mg/kg, s.c.). S16924 (0.05 mg/kg, s.c.), S18327 (0.09 mg/kg, s.c.), quetiapine (1.8 mg/kg, s.c.), risperidone (0.02 mg/kg, s.c.) and ziprasidone (0.01 mg/kg, s.c.), antipsychotics which possess-like clozapine-marked affinity for 5-HT(2A) versus D(2) receptors, also generalized to MDL100,907. In distinction, raclopride, an antipsychotic which selectively interacts with D(2) versus 5-HT(2A) receptors, did not display significant generalization. Interestingly, haloperidol, which shows only modest affinity for 5-HT(2A) versus D(2) sites, generalized to MDL100,907 (ED(50), 0.02 mg/kg, s.c.). In light of the antagonist properties of haloperidol, clozapine and all other antipsychotics tested (except raclopride) at alpha(1)-adrenoceptors (ARs), the selective alpha(1)-AR antagonists, prazosin and WB4101, were examined. Both dose-dependently and fully generalized to MDL100,907 (ED(50)s, 0.07 and 0.11 mg/kg, s.c., respectively). At doses showing pronounced generalization to MDL100,907, the only drugs which significantly suppressed response rates were haloperidol and, weakly, quetiapine. Raclopride also markedly decreased response rates. In conclusion, the antipsychotic agents, clozapine, ziprasidone, risperidone, S16924, S18327, quetiapine and haloperidol, all generalized to a DS elicited by MDL100,907. While D(2) receptors are not implicated in their actions, in addition to antagonist properties at 5-HT(2A) receptors, blockade of alpha(1)-ARs and other, as yet unidentified, mechanisms may be involved. These data underpin interest in MDL100,907 as a potential antipsychotic agent.     

Lack of specific effects of selective D(1) and D(2) dopamine antagonists vs. risperidone on morphine-induced hyperactivity

In the present study, three different dopamine antagonists were challenged in order to counteract hyperactivity induced by 50 mg/kg of morphine. A wide range of doses of morphine (50, 25, 12.5, 6.25, or 3.12 mg/kg) were evaluated on spontaneous locomotor activity. A significant increase was observed only with the two higher doses tested (25 and 50 mg/kg). No decrease was found with any of the doses used at any period of time. After analyzing doses of SCH 23390 (0.5, 0.1, and 0.05 mg/kg), raclopride (0.5, 0.25, and 0.125 mg/kg) and risperidone (0.1, 0.05, and 0.025 mg/kg) administered alone, only the 0.5 mg/kg dose of SCH 23390 decreased locomotor activity. The three compounds counteracted morphine-induced hyperactivity, but with SCH 23390 it was only achieved with the dose of 0.5 mg/kg, which also decreased spontaneous locomotor activity and induced catalepsy. On the other hand, raclopride and risperidone neutralized morphine-induced hyperactivity at doses that did not affect locomotor activity, although the former induced catalepsy when administered with morphine. It is concluded that although the blockade of D(1) and D(2) DA receptors decreases morphine-induced hyperactivity, this action is not specific, contrary to the action of risperidone, which counteracts this hyperactivity without any other motor effects.     

Adjunctive galantamine, but not donepezil, enhances the antipsychotic-like effect of raclopride in rats

Acetylcholine (ACh) esterase inhibitors like galantamine and donepezil have been tested as adjunct treatment in schizophrenia. Although ACh esterase inhibition might confer some antipsychotic activity, the role of allosteric potentiation of nicotinic ACh receptors (nAChRs), which is an additional mechanism of galantamine, remains elusive. Therefore, the potential antipsychotic-like effects of galantamine and donepezil, respectively, alone, and in combination with the dopamine D2/3 receptor antagonist, raclopride, were tested in the conditioned avoidance response (CAR) test and extrapyramidal side-effect liability was assessed with the catalepsy test. Neither galantamine nor donepezil alone suppressed CAR selectively. Galantamine, but not donepezil, enhanced the raclopride-induced suppression of CAR, predicting augmentation of antipsychotic activity. In contrast to donepezil, galantamine did not increase catalepsy, alone or combined with raclopride. These data suggest that allosteric potentiation of nAChRs may mediate the antipsychotic-like effect of adjunctive galantamine and provide support for the development of alpha7 nAChR-selective allosteric potentiators for schizophrenia.